Deep-seated mycoses are being increasingly observed in immunocompromised patients and in patients receiving aggressive cancer chemotherapy. The use of available drugs for the treatment of these infections are limited by toxicity and the emergence of resistant fungal species. The impact of fungal infections in the clinical management of immunocompromised patients underscore the clear need for new antifungals. Historically microorganisms and plants have been rich sources of drugs for the treatment of human disease. Many of these organisms have been screened numerous times, decreasing the probability of finding additional lead compounds. One way to avoid this stumbling block is to screen microorganisms from unusual and ignored ecosystems. Thermophilic organisms from unique ecosystems represent an unscreened source of potential bioactive compounds. The overall goal of this project is to identify new antifungal compounds isolated form thermophilic microorganisms. In the Phase I work, we have identified thermophiles that have potent activity against several human fungal pathogens and have identified an ascribed fungal-specific mechanism of action. In this Phase II proposal, we plan to extend the Phase I work by screening additional extremophiles, elucidating the structures of ten antifungal compounds and testing five of these compounds in pre-clinical animal models. PROPOSED COMMERCIAL APPLICATION The research and development outlined in the Phase II SBIR proposal will lead to the identification of a number of lead antifungal compounds. We estimate that the market potential for a novel and safe antifungal drug to be greater than 200,000,000 dollars per year.